Research: Our research group is interested in studying the genetic basis for thoracic and head and neck cancers. We had recently discovered the etiologic basis for the most common malignant salivary gland cancer and in the past year we have we have defined the mechanism of tumorigenesis of this new activated oncogene called Mect1-Maml2. This data confirmed the activation of cAMP/CREB regulated genes by the Mect1-Maml2 fusion product and provides a direct genetic link between deregulation of cAMP/CREB pathways and epithelial tumorigenesis. Importantly, the Mect1 gene has now be identified as a member of a new potent CREB co-activator family (now called CRTC for CREB-regulated transcription coactivator). CRTC family members are essential components of glucose control mechanisms during starvation and have now been shown to mediate the activity of many common anti-diabetes drugs. In addition, the tumor suppressor gene LKB1, which underlies the Peutz-Jegher colon cancer syndrome and selected sporadic lung and colon cancer samples, regulates normal Mect1/CRTC function which emphasizes unexpected links between our discovery of the Mect1 gene and many other cancer types. We are currently studying LKB1 and Mect1 function in different head and neck cancer, salivary cancer, and lung cancer samples to define the role for the LKB1/Mect1 cancer pathway. In the past year, we have also reported that sustained expression of Mect1-Maml2 is essential for the viability and growth of tumors with deregulated Mect1 function. This data supports the role of the Mect1 cancer gene pathway as an important therapeutic target for malignant salivary gland cancers and also emphasizes the remarkable specificity of new RNAi technology which exhibits cellular toxicity only if the Mect1 gene has been rearranged and activated. In the past year, the Mect1-Maml2 oncogene has been extensively confirmed as the most important diagnostic and prognostic marker for these tumors. We have also begun an effort to identify the etiologic basis for other subtypes of malignant salivary gland cancer which do not express the Mect1-Maml2 oncogene. This work continues an important collaboration between the NCI, NIH and the Naval Hospital, Bethesda to study the genetic basis for human cancers that lack known effective treatments and which are not adequately investigated in the extramural research community. Another research goal under our project to "study the mechanism of oncogene activation" in thoracic tumors, is a comprehensive analysis of the genetic and biological basis for malignant mesothelioma. Using extramural collaborations we are analyzing the RB/p16, NF2/merlin pathways, and other novel cancer pathways in a large collection of mesothelioma samples collected at the NCI and Naval Hospital. These data will provide clues for additional investigations to provide further insights into diagnosis and therapy for this difficulty malignancy.